The concept of cyclophasic hormonal regimens comprising estrogens and progestins is disclosed by Robert Casper in U.S. Pat. Nos. 5,108,995; 5,256,421; and 5,276,022. The disclosures of these three U.S. Patents are hereby incorporated herein by reference.
The primary aim of both the oral contraception (OC) hormone replacement therapy (HRT) and cyclophasic regimens disclosed by Casper is to induce higher levels of progestin and estrogen receptors by an estrogen-induced increase in receptor production. The greater concentration of steroid receptors increases the sensitivity of the target organs to progestin and estrogen and allows the use of lower doses of exogenous steroids. The cyclophasic regimens of Casper upregulate the estrogen and progestin receptors in an estrogen-dominant phase of 2-4 days and then down-regulate the same receptors in a progestin-dominant phase in the next 2-4 days. In contrast to conventional oral contraception regimens which are continuously progestin-dominant, the levels of the estrogen and progestin receptors are continuously down-regulated. In both phases of the cyclophasic regimen, the estrogen dose is constant while the progestin dose is varied to produce relatively progestin-dominant or estrogen-dominant effects. These alternating phases continue without interruption for HRT but with OC, they are interrupted periodically for 4-7 days to allow menstrual bleeding to occur.
Norethindrone may be used in trials of cyclophasic phasic regimens and has a relatively short half-life. In pharmacokinetic models for contraceptive cyclophasic regimens longer half-lives for some progestin (e.g., norgestimate) given in the progestin-dominant phase is observed to cause higher than intended progestin levels to extend into the estrogen-dominant phase. This effect may indicate that a sufficiently estrogen-dominant phase is not achieved and the steroid receptors are not adequately upregulated. Without adequate upregulation, the steroid doses administered in a cyclophasic regimen are too low to maintain endometrial integrity and breakthrough bleeding rates higher than those resulting from administration of standard dose oral contraceptives have been observed in clinical trials.
An antiprogestin added to all or part of the estrogen-dominant phase of a cyclophasic regimen acts more quickly to increase the receptor levels in the estrogen-dominant phase. The mechanisms of action for this effect may be two-fold. An antiprogestin directly antagonizes the progestin receptor-binding of a progestin and prevents receptor down-regulation by the progestin. In the absence of exogenous progestin and estrogen, antiprogestins have been shown to upregulate progestin and estrogen receptors in human endometrial tissue. Following physiologic estrogen replacement in ovarectonized monkeys, antiprogestin treatment (e.g. using an antiprogestin known as RU486) induces dramatic dose-dependent rise in estradiol receptor concentrations. Despite the rise in estrogen receptor levels, an antiprogestin (RU486) inhibited endometrial proliferation and secretory activity. See Wolf et al. Fertility and Sterility, Vol 52. No. 6 December 1989 pp 1055-1060 and Neulen et al. J. Clinical Endocrinology and Metabolism, Vol. 71 No. 4, 1990 pp. 1074-1075. Low doses of an antiprogestin (10-50 mg RU486) administered in continuous or intermittent periods during the menstrual cycle inhibit ovulation. See Spitz et al. Fertility and Sterility, Vol. 59, No. 5, pp. 971-975.
It is therefore an object of the present invention to provide a cyclophasic hormonal regimen comprising the administration of antiprogestin which overcomes problems of breakthrough bleeding and/or excessive endometrial mitotic activity resulting in endometrial hyperplasia. It is an additional object of the present invention to progress beyond the prior art and provide novel cyclophasic regimens utilizing antiprogestin compounds for contraception and hormone replacement therapy. Additional objects and advantages of the invention will be set forth, in part in the description which follows and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention are realized and obtained by means of the devices, combinations, and methods particularly pointed out in the appended claims.